Compounds of formula (1): ##STR2##
in which P.sup.1 and P.sup.2 are protecting groups are useful as intermediates for preparing compounds of formula (2). ##STR3##
wherein R is C.sub.1-4 alkyl or C.sub.1-4 haloalkyl, and salts therof e.g. the dihydrochloride salts;
which are in turn useful as intermediates for preparing quinolone antibiotics, such as those disclosed in U.S. Pat No. 5,633,262 and EP 688772A1. The intermediate of formula (2) in which R is methyl is of particular use in the production of the compound (R,S)-7-(3-aminomethyl-4-methoxyiminopyrrolidin-1-yl)-1-cyclopropyl-6-fluo ro-4-oxo-1,4-dihydro-1,8-n aphthyridine-3-carboxylic acid and salts thereof, especially (R,S)-7-(3-aminomethyl-4-syn-methoxyimino-pyrrolidin-1-yl)-1-cyclopropyl-6 -fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid methanesulfonate and hydrates thereof including the sesquihydrate disclosed in WO 98/42705. PA1 a) The process is somewhat inefficient since the use of a reducing agents, such as, platinum under hydrogen atmosphere, palladium metal, lithium aluminum hydride(LAH), lithium borohydride(LiBH.sub.4), sodium borohydride(NaBH.sub.4), or NaBH.sub.4 -trifluoroacetic acid complex, etc., reduces both the ketone and cyano groups, requiring reoxidation of the alcohol to regenerate the ketone. PA1 b) Reducing agents other than NaBH.sub.4 -trifluoroacetic acid complex do not completely reduce the cyano group, resulting in the production of several side products and thus a reduction in yield and purity. Although the use of NaBH.sub.4 -trifluoroacetic acid complex as a reducing agent may improve the yield and purity of the product, its use results in the discontinuous generation of hydrogen gas. Therefore, explosion risk cannot be adequately prevented by simple exhaust-incineration equipment, and it is not easy to apply this reduction process to production on a large scale. In addition, since the process for preparing the complex itself has many problems, such as formation of side products, etc., it is inappropriate for use on a large scale. PA1 c) Side reactions which are not observed in small scale production occur more frequently in a large scale production which leads to a reduction in yield. The undesired side products, some of which are not clearly identified, make the separation and/or purification of the desired product difficult. Side products which have been identified include the compound of formulae (3) and (4): ##STR5## PA1 d) The pyridine-sulfur trioxide complex used during the oxidation of the hydroxy group is expensive, making it unsuitable for use on an industrial or commercial scale. In addition, the dimethylsulfide formed as a side product during the oxidation is not environmentally acceptable. PA1 e) When a transition metal catalyst such as platinum is used in hydrogenation reaction, the reaction does not well proceeded using a catalytic amount of platinum and a low pressure of hydrogen, and thus cannot be used commercially. PA1 a) reaction of a compound of formula (5): ##STR7## PA1 b) protecting the amino group to produce a compound of formula (7): ##STR9## PA1 c) selective reduction of the double bond to produce the compound of formula (1).
EP 688772A1 discloses a process for the production of a compound of formula (2) as depicted in Scheme 1: ##STR4##
in Scheme 1 Boc represents t-butoxycarbonyl, and has the same meaning throughout the present specification.
There are however several drawbacks with the process of scheme 1, particularly if it is to be used on a tens to hundreds of kilogramme scale for commercial production, these include:
It is assumed that the side products (3) and (4) are produced by reactions of the starting 4-cyano-1-(N-t-butoxy-carbonyl)pyrrolidin-3-one with sodium borohydride and trifluoroacetic acid. The by-product of formula (3) is particularly troublesome as it is not easily removed by recrystallization.
Thus, it is desirable to find an alternative process for the production of the compounds of formulae (1) and (2), particularly one in which an .alpha.-cyanoketone derivative can be selectively reduced in such a way that the subsequent reoxidation of the hydroxy group is not required.
The present invention is based on the finding that the cyano group of an .alpha.-cyanoketone derivative can be selectively reduced to effectively produce the compound of formula (1) using Raney-nickel under hydrogen as reducing agent. The reaction conditions used in this process are very mild and thus can be used for industrial production. The use of a Raney-nickel catalyst gives several advantages over the prior art process described above, for example it does not require the additional oxidation reaction, also, the formation of side products markedly decreases compared with the process using NaBH.sub.4 as a reducing agent, which leads to a stoichiometric reaction and a good yield.